Preparation method of 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole

Abstract

The invention discloses a preparation method of 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole, which comprises the following steps: reacting 4-methyl thiosemicarbazide with pivaloyl chloride under the action of a cyclization dehydrating agent S to prepare 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole hydrochloride, and reacting the 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole hydrochloride with the pivaloyl chloride under the action of the cyclization dehydrating agent S to prepare the 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole. The preparation method comprises the following steps: reacting 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole hydrochloride with an alkali to prepare 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole, and reacting the 2-methylamino-5-tert-butyl-1, 3, 4-thiadiazole hydrochloride with the alkali to prepare 2-methylamino-5- Wherein the cyclization dehydrating agent S comprises at least one of trimethylacetic anhydride and solid superacid containing zirconium dioxide. The novel cyclization dehydrating agent S is introduced, so that the treatment problem of wastewater containing phosphorus, acid and the like in the traditional technology is solved; meanwhile, the recycled organic solvent and the cyclization dehydrating agent S regenerated and converted from the cyclization dehydrating agent S derivative can be recycled, so that the production cost is greatly reduced, and the waste discharge is reduced; the preparation method has the advantages of few by-products, high yield and safe and simple process operation, meets the requirements of modern green and clean production process, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and in particular relates to a preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Background Art

[0002] Tebuthiuron is a non-selective substituted urea, which is a systemic and non-selective herbicide. It can exert herbicidal activity by inhibiting the PSII receptor site of the electron transport chain in photosynthesis. It is mainly used to control annual and perennial grasses, broad-leaved weeds and shrubs in sugarcane fields, pastures and non-cultivated lands. In recent years, the global demand for herbicides is very large. Among them, tebuthiuron technical and related formulated products account for a large market share, and the product has good future prospects.

[0003] 2-Methylamino-5-tert-butyl-1,3,4-thiadiazole is a key intermediate for the production of tebuthiuron. Its traditional preparation method is as follows: 4-methylaminothiourea and pivalic acid or pivaloyl chloride are cyclized with a dehydrating agent to obtain a 2-methylamino-5-tert-butyl-1,3,4-thiadiazole salt, and then alkalized to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. However, in this type of method, the mainstream selection of dehydrating agents is phosphorus-containing reagents, sulfuric acid, phosgene reagents or a mixture of the former several. For example, US patents with publication numbers US4283543A, US3887572A, US3803164A, etc. and Chinese patents with publication number CN104610250A, etc. report the use of polyphosphoric acid, phosphorus oxychloride, sulfuric acid, etc. for cyclization dehydration, but their reaction conditions are harsh, difficult to control, and will produce a large amount of phosphorus-containing and acid-containing wastewater, which is difficult to treat and highly polluting, and does not meet the requirements of the green and clean production process; for example, the Chinese patent with publication number CN105524017A reports the use of solid phosgene, dichlorophosgene, phosgene, etc. for cyclization dehydration, but phosgene reagents are highly toxic, and the use of phosgene reagents also has relatively high requirements for production equipment, and this type of process does not conform to the direction of green production development.

[0004] With the innovation and development of technology, some new methods have emerged in the industry. For example, Chinese patents with publication numbers CN109251188A, CN118638076A, etc. report the use of pivaloyl chloride for cyclization and dehydration. The former adds pivaloyl chloride in two batches, but there are problems such as stirring failure and runaway temperature during the experimental verification process. The latter is based on the scheme recorded by Shi Rongchao et al. [Chemical World, 2019, 60(10): 706-710] (i.e., adding an excessive amount of pivaloyl chloride at one time), and a dehydration reaction catalyst is added to solve the problems of stirring failure and runaway temperature. However, substances such as vanadium pentoxide, silicon dioxide, aluminum oxide, and titanium dioxide are introduced in this scheme, and an excessive amount of pivaloyl chloride still needs to be added for the dehydration reaction. Substances such as vanadium pentoxide, silicon dioxide, aluminum oxide, and titanium dioxide only play a catalytic role. Chinese patent with publication number CN110372634A reports that using pivalic acid and hydrazine hydrate as raw materials, through catalytic condensation and dehydration with tetrabutyl titanate or tetraisopropyl titanate, reacting with ammonium thiocyanate, then through cyclization and dehydration with concentrated sulfuric acid, reacting with paraformaldehyde, and then through catalytic hydrogenation reduction with Raney nickel or palladium-carbon to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Although this method provides a new idea for synthesizing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, it has more reaction steps, involves the use of catalysts such as tetrabutyl titanate or tetraisopropyl titanate, Raney nickel or palladium-carbon, with higher costs, and the overall yield of this route is relatively low, and its industrial value is relatively low. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole.

[0006] The technical solution adopted by the present invention is: a preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, the steps of which include: reacting 4-methylaminothiourea with pivaloyl chloride under the action of a cyclization dehydrating agent S to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride; reacting 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride with a base to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole; wherein, the cyclization dehydrating agent S includes at least one of pivalic anhydride and solid superacid containing zirconium dioxide.

[0007] Preferably, the molar ratio of the feed of 4-methylaminothiourea to pivaloyl chloride is 1.0: (1.0 - 1.2).

[0008] Preferably, the molar ratio of the feed of 4-methylaminothiourea to pivalic anhydride is 1.0: (1.0 - 1.2), or: the mass ratio of the feed of 4-methylaminothiourea to solid superacid containing zirconium dioxide is 1.0: (0.05 - 0.10).

[0009] Preferably, when preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, 4-methylaminothiourea, pivaloyl chloride and the cyclodehydrating agent S react in an organic solvent, and the organic solvent includes at least one of benzene, toluene, xylene, acetonitrile, petroleum ether, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane.

[0010] Preferably, after 4-methylaminothiourea, pivaloyl chloride and the cyclodehydrating agent S react in an organic solvent, a mixture of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, a derivative of the cyclodehydrating agent S and the organic solvent is obtained.

[0011] Preferably, the mass ratio of the organic solvent to 4-methylaminothiourea in the feed is (2.0 - 6.0):1.0.

[0012] Preferably, when preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, the reaction temperature is 50 - 90 °C and the reaction time is 3 h - 6 h.

[0013] Preferably, after 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with the base, the pH is 7 - 8.

[0014] Preferably, the base is an organic base or an inorganic base. The organic base includes at least one of pyridine, triethylamine, ammonia water, 4-dimethylaminopyridine and N,N-diisopropylethylamine, and the inorganic base includes at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.

[0015] Preferably, after 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with the base, an extraction solvent is added to extract 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, and the extraction solvent includes toluene.

[0016] The advantages and positive effects of the present invention are as follows: By introducing a new cyclodehydrating agent S to replace reagents such as phosphorus oxychloride, polyphosphoric acid, and concentrated acid in the traditional method, the problem of treating wastewater containing phosphorus and acid is completely solved; at the same time, the derivative of the cyclodehydrating agent S is converted into the cyclodehydrating agent S for recycling, and the rectified and recovered organic solvent can also be directly recycled, which can greatly reduce the production cost and reduce waste emissions; at the same time, the by-products of this preparation method are few and the yield is high (the yield can reach 96% and the purity is above 98%). The process operation is safe and simple, meeting the requirements of modern green and clean production processes and suitable for industrial production. Detailed Embodiments

[0017] The embodiments of the present invention will be described below.

[0018] This embodiment provides a method for preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. In this preparation method: 4-methylaminothiourea reacts with pivaloyl chloride under the action of cyclodehydrating agent S to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride; 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with a base to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole; wherein, cyclodehydrating agent S includes at least one of pivalic anhydride and solid superacid containing zirconia. Among them, the generated pivalic acid can be recycled to prepare pivalic anhydride for recycling. The solid superacid containing zirconia has acidic catalytic dehydration under heating conditions and can carry out cyclodehydration during this reaction process, and its derivative - zirconia during the cyclodehydration process can be recycled and regenerated.

[0019] The chemical reaction formula of the above method is as follows:

[0020]

[0021] When preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, 4-methylaminothiourea, pivaloyl chloride and cyclodehydrating agent S are reacted in an organic solvent. The organic solvent includes at least one of benzene, toluene, xylene, acetonitrile, petroleum ether, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane. These organic solvents do not affect and do not participate in the above reaction.

[0022] Among them, the organic solvent is preferably toluene, and the mass ratio of the organic solvent to 4-methylaminothiourea in the feed is (2.0 - 6.0):1.0, preferably (2.0 - 4.0):1.0.

[0023] When preparing 2-methylamino-5-tert-butyl-1, ,4-thiadiazole hydrochloride, the molar ratio of 4-methylaminothiourea to pivaloyl chloride in the feed is 1.0:(1.0 - 1.2). After a large number of experimental explorations and verifications, it is preferably 1.0:(1.0 - 1.1); the molar ratio of 4-methylaminothiourea to cyclodehydrating agent S in the feed is 1.0:(1.0 - 1.2). After a large number of experimental explorations and verifications, it is preferably 1.0:(1.0 - 1.1).

[0024] When preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, the reaction temperature should be controlled at 50 - 90 °C. After a large number of experimental explorations and verifications, it is preferably 50 - 70 °C, and the reaction time should be controlled at 3h - 6h.

[0025] After 4-methylaminothiourea, pivaloyl chloride and pivalic anhydride react in an organic solvent, the mixture in the reaction kettle is cooled to room temperature and then filtered. The obtained filter cake is 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride. The filtrate obtained is rectified to recover the organic solvent and the pivalic anhydride derivative - pivalic acid. Pivalic acid can be converted into pivalic anhydride and used for the above cyclization and dehydration again. The organic solvent recovered by rectification can also be directly recycled. The advantage of using pivalic anhydride is that due to the presence of the steric hindrance group tert-butyl, impurities generated during the reaction can be avoided, which affects the purity and yield. In the continuous exploration of the inventor, it is found that a solid superacid containing zirconia can also achieve the same or better reaction effect as above, and the obtained filter cake contains zirconia, which can also be separated and regenerated after subsequent alkalization for recycling. The above technical solution can greatly reduce the production cost and reduce waste emissions, meeting the requirements of modern green and clean production processes and being suitable for industrial production.

[0026] When preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, an alkali is added to 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride to adjust the pH to 7-8.

[0027] The above alkali can be an organic base or an inorganic base. The organic bases include at least one of pyridine, triethylamine, ammonia water, 4-dimethylaminopyridine and N,N-diisopropylethylamine. The inorganic bases include at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate. In this embodiment, the above alkali is preferably sodium carbonate or sodium bicarbonate.

[0028] After the reaction of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride with the alkali, an extraction solvent is added to extract 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. The extraction solvent is preferably toluene. After extraction, liquid separation, desolvation of the organic solvent and drying, 2-methylamino-5-tert-butyl-1,3,4-thiadiazole is obtained.

[0029] By adopting the above technical solution, by introducing a new cyclization and dehydration agent S to replace reagents such as phosphorus oxychloride, polyphosphoric acid, and concentrated acid in the traditional method, the problem of treating waste water containing phosphorus and acid is completely solved; at the same time, the derivative of the cyclization and dehydration agent S is converted into the cyclization and dehydration agent S for recycling, and the organic solvent recovered by rectification can also be directly recycled, which can greatly reduce the production cost and reduce waste emissions; at the same time, the by-products of this preparation method are few, the yield is high (the yield can reach 96%, and the purity is above 98%), the process operation is safe and simple, meeting the requirements of modern green and clean production processes and being suitable for industrial production.

[0030] The following are some specific examples. For the experimental methods without specific operation steps described, they are all carried out according to the corresponding product specifications. The instruments, reagents, and consumables used in the examples can be purchased from commercial companies without special instructions.

[0031] Example 1: Preparation of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole

[0032] In a 1000 mL four-necked round-bottom flask, add 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea, add 220 g of the organic solvent toluene, and simultaneously dropwise add a mixed solution of 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride and 193.85 g (purity 98%, 1.02 mol) of pivalic anhydride. Control the reaction temperature of the system between 50 and 55 °C, react for 4 h, and end the reaction until no raw materials are detected by HPLC monitoring.

[0033] Lower the temperature of the above reaction system to room temperature, filter to obtain a filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, and recover the organic solvent and pivalic acid by fractional distillation of the filtrate.

[0034] Adjust the pH of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride to 7 - 8 with saturated sodium bicarbonate solution, extract and separate with 350 g of the extraction solvent toluene, then carry out desolvation of the organic solvent and drying to obtain a white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity is tested to be 98%, the yield is 166.02 g (0.95 mol), and the calculated yield is 95%.

[0035] Example 2: Preparation of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole

[0036] In a 1000 mL four-necked round-bottom flask, add 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea, add 440 g of the organic solvent toluene, and simultaneously dropwise add a mixed solution of 126.73 g (purity 98%, 1.03 mol) of pivaloyl chloride and 195.75 g (purity 98%, 1.03 mol) of pivalic anhydride. Control the reaction temperature of the system between 55 and 60 °C, react for 3 h, and end the reaction until no raw materials are detected by HPLC monitoring.

[0037] Lower the temperature of the above reaction system to room temperature, filter to obtain a filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, and recover the organic solvent and pivalic acid by fractional distillation of the filtrate.

[0038] Adjust the pH of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride to 7-8 with saturated sodium bicarbonate solution, extract and separate with 350 g of extraction solvent toluene, then carry out organic solvent desolvation and drying to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Test its purity to be 98%, the yield is 167.76 g (0.96 mol), and calculate its yield to be 96%.

[0039] Example 3: Preparation of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole

[0040] In a 1000 mL four-necked round-bottom flask, add 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea, add 330 g of organic solvent toluene, and simultaneously dropwise add a mixed solution of 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride and 193.85 g (purity 98%, 1.02 mol) of pivalic anhydride. Control the reaction temperature of the system between 60-65 °C, react for 3 h, and end the reaction until no raw materials are detected by HPLC monitoring of the reaction.

[0041] Lower the temperature of the above reaction system to room temperature, filter to obtain a filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, and recover the organic solvent and pivalic acid from the filtrate by fractional distillation.

[0042] Adjust the pH of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride to 7-8 with saturated sodium bicarbonate solution, extract and separate with 350 g of extraction solvent toluene, then carry out organic solvent desolvation and drying to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Test its purity to be 98%, the yield is 168.11 g (0.96 mol), and calculate its yield to be 96%.

[0043] Example 4: Preparation of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole

[0044] In a 1000 mL four-necked round-bottom flask, add 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea, add 220 g of organic solvent toluene, add 11.07 g of solid superacid containing zirconia, and dropwise add 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride. Control the reaction temperature of the system between 65-70 °C, react for 3 h, and end the reaction until no raw materials are detected by HPLC monitoring of the reaction.

[0045] Lower the temperature of the above reaction system to room temperature, filter to obtain a filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, and its filtrate can be directly applied to the next batch of reactions.

[0046] The filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with 350 g of extraction solvent toluene, filtered to obtain zirconia solid, the filtrate was separated by liquid-liquid extraction, and then the organic solvent was removed by evaporation and dried to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity was tested to be 98%, the yield was 169.51 g (0.97 mol), and the calculated yield was 97%.

[0047] Comparative Example 1:

[0048] In a 1000 mL four-necked round-bottom flask, 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea was added, 220 g of organic solvent toluene was added, and a mixed solution of 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride and 193.85 g (purity 98%, 1.02 mol) of pivalic anhydride was added dropwise simultaneously. The reaction temperature of the system was controlled between 70-75 °C, and the reaction was carried out for 3 h. After the reaction was monitored by HPLC and no raw materials were detected, the reaction was terminated.

[0049] The temperature of the above reaction system was lowered to room temperature, and the filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was obtained by filtration. The filtrate was separated by distillation to recover the organic solvent and pivalic acid.

[0050] The 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with 350 g of extraction solvent toluene, separated by liquid-liquid extraction, and then the organic solvent was removed by evaporation and dried to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity was tested to be 93%, the yield was 169.42 g (0.92 mol), and the calculated yield was 92%.

[0051] Comparative Example 2:

[0052] In a 1000 mL four-necked round-bottom flask, 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea was added, 220 g of organic solvent toluene was added, and a mixed solution of 147.65 g (purity 98%, 1.20 mol) of pivaloyl chloride and 228.06 g (purity 98%, 1.20 mol) of pivalic anhydride was added dropwise simultaneously. The reaction temperature of the system was controlled between 70-75 °C, and the reaction was carried out for 3 h. After the reaction was monitored by HPLC and no raw materials were detected, the reaction was terminated.

[0053] The temperature of the above reaction system was lowered to room temperature, and the filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was obtained by filtration. The filtrate was separated by distillation to recover the organic solvent and pivalic acid.

[0054] The 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was adjusted to pH 7 - 8 with saturated sodium bicarbonate solution, extracted and separated with 350 g of extraction solvent toluene, then the organic solvent was removed by evaporation and dried to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity was tested to be 92%, the yield was 167.54 g (0.90 mol), and the calculated yield was 90%.

[0055] Comparative Example 3:

[0056] In a 1000 mL four-necked round-bottom flask, 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea was added, 330 g of organic solvent toluene was added, 11.07 g of solid superacid containing zirconia was added, and 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride was added dropwise. The reaction temperature of the system was controlled between 75 - 80 °C, and the reaction was carried out for 3 h. After the reaction was monitored by HPLC and no raw materials were detected, the reaction ended.

[0057] The temperature of the above reaction system was lowered to room temperature, and the filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was obtained by filtration. The filtrate could be directly applied to the next batch of reactions.

[0058] The filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was adjusted to pH 7 - 8 with saturated sodium bicarbonate solution, extracted and filtered with 350 g of extraction solvent toluene to obtain solid zirconia. The filtrate was separated, and then the organic solvent was removed by evaporation and dried to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity was tested to be 98%, the yield was 162.52 g (0.93 mol), and the calculated yield was 93%.

[0059] Comparative Example 4:

[0060] In a 1000 mL four-necked round-bottom flask, 110.69 g (purity 95%, 1.00 mol) of 4-methylaminothiourea was added, 550 g of organic solvent toluene was added, and a mixed solution of 125.50 g (purity 98%, 1.02 mol) of pivaloyl chloride and 193.85 g (purity 98%, 1.02 mol) of pivalic anhydride was added dropwise simultaneously. The reaction temperature of the system was controlled between 60 - 65 °C, and the reaction was carried out for 3 h. After the reaction was monitored by HPLC and no raw materials were detected, the reaction ended.

[0061] The temperature of the above reaction system was lowered to room temperature, and the filter cake containing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was obtained by filtration. The filtrate was separated by distillation to recover the organic solvent and pivalic acid.

[0062] The 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted and separated with 350 g of extraction solvent toluene, then the organic solvent was removed by evaporation and dried to obtain white solid of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole. Its purity was tested to be 98%, the yield was 167.98 g (0.96 mol), and the calculated yield was 96%.

[0063] According to the results of Comparative Examples 1-2, after detecting and analyzing each batch of materials with higher impurities, it was found that when pivalic anhydride was used as the cyclodehydrating agent S, an increase in the feed ratio would cause pivaloyl chloride or pivalic anhydride to continue to react with the generated target compound under heating conditions, generating impurities; according to the results of Comparative Example 3, when using a solid superacid containing zirconia as the cyclodehydrating agent S, due to its extremely strong acidity, more tar would be produced when the temperature was increased for the reaction, affecting the purity and yield of the product. According to the results of Comparative Example 4, using a larger mass ratio of the organic solvent toluene could also obtain similar yields and purities. Therefore, to save the organic solvent, its amount was 2.0-4.0 times the feeding mass of 4-methylaminothiourea.

[0064] The above are only the preferred embodiments of the present invention and do not impose any form of limitation on the present invention. Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make many possible changes and modifications to the technical solution of the present invention, or modify it into an equivalent embodiment with equivalent changes, without departing from the spirit and technical solution of the present invention. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, characterized in that: 4-Methylaminothiourea reacts with pivaloyl chloride under the action of cyclodehydrating agent S to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride; 2-Methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with a base to obtain 2-methylamino-5-tert-butyl-1,3,4-thiadiazole; wherein, the cyclodehydrating agent S includes at least one of pivalic anhydride and solid superacid containing zirconia.

2. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 1, characterized in that: The molar ratio of 4-methylaminothiourea to pivaloyl chloride is 1.0:(1.0 - 1.2).

3. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 1 or 2, characterized in that: The molar ratio of 4-methylaminothiourea to pivalic anhydride is 1.0:(1.0 - 1.2), or: the mass ratio of 4-methylaminothiourea to solid superacid containing zirconia is 1.0:(0.05 - 0.20).

4. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 3, characterized in that: When preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, 4-methylaminothiourea, pivaloyl chloride and the cyclodehydrating agent S react in an organic solvent, and the organic solvent includes at least one of benzene, toluene, xylene, acetonitrile, petroleum ether, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane.

5. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 4, characterized in that: After 4-methylaminothiourea, pivaloyl chloride and the cyclodehydrating agent S react in an organic solvent, a mixture of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, cyclodehydrating agent S derivative and organic solvent is obtained.

6. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 4 or 5, characterized in that: The mass ratio of the organic solvent to 4-methylaminothiourea is (2.0 - 6.0):1.

0.

7. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 6, wherein: When preparing 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride, the reaction temperature is 50 - 90 °C and the reaction time is 3 h - 6 h.

8. A preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to any one of claims 1-2, 4-5, and 7, characterized in that: After 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with the base, the pH is 7 - 8.

9. The preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to claim 8, characterized in that: The base is an organic base or an inorganic base. The organic base includes at least one of pyridine, triethylamine, ammonia water, 4-dimethylaminopyridine and N,N-diisopropylethylamine, and the inorganic base includes at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.

10. A preparation method of 2-methylamino-5-tert-butyl-1,3,4-thiadiazole according to any one of claims 1-2, 4-5, 7, 9, characterized in that: After 2-methylamino-5-tert-butyl-1,3,4-thiadiazole hydrochloride reacts with the base, an extraction solvent is added to extract 2-methylamino-5-tert-butyl-1,3,4-thiadiazole, and the extraction solvent includes toluene.

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